HIV, or human immunodeficiency virus, is a virus that targets cells in the immune system.
Over time, the immune system begins to fail which is called immunodeficiency, and this
increases the risk of infections and tumors that a healthy immune system would usually
be able to fend off.
These complications are referred to as AIDS, or acquired immunodeficiency syndrome.
Now there are two distinct types of HIV—HIV-1 and HIV-2.
HIV-1 is the more commonly associated with AIDS in the US and worldwide, HIV-2 is more
rare, and typically restricted to areas in western Africa and southern Asia.
HIV-2 is so uncommon that “HIV” almost always refers to HIV-1.
Alright HIV targets CD4+ cells, meaning cells that have this specific molecule called CD4
on their membrane.
Macrophages, T-helper cells, and dendritic cells are all involved in the immune response
and all have CD4 molecules; therefore they can be targeted by HIV.
The CD4 molecule helps these cells attach to and communicate with other immune cells,
which is particularly important when the cells are launching attacks against foreign pathogens.
So this little molecule is pretty important for our immune system, but it’s also extremely
important for HIV.
HIV targets and attaches to the CD4 molecule via a protein called gp120 found on its envelope.
HIV then again uses gp120 to attach to another receptor, called a co-receptor.
HIV needs to bind to both the CD4 molecule and a coreceptor to get inside the cell.
The most common co-receptors that HIV uses are the CXCR4 co-receptor, which is found
mainly on T-cells, or the CCR5 co-receptor which is found on T-cells, macrophages, monocytes,
and dendritic cells.
These coreceptors are so important that some people with homogeneous genetic mutations
in their CCR5 actually have resistance or immunity to HIV, since HIV can’t attach
and get into the cell.
In fact, even heterozygous mutations which lead to fewer co-receptors on the cells, can
make it harder for the virus to spread, and results in a slower disease progression.
For those without this mutation though, once HIV binds to CD4 and either CCR5 or CXCR4,
it gains access to the cell.
HIV is a single-stranded, positive-sense, enveloped RNA retrovirus, meaning that it
injects its single strand of RNA into the T-helper cell.
The “retro” part of retrovirus isn’t referring to its style, but refers to it needing
to use an enzyme called reverse transcriptase to transcribe a complementary double-stranded
piece of “proviral” DNA.
Proviral just means that it’s ready to be integrated into the host’s DNA, so it enters
the T-helper cell’s nucleus and pops itself into the cell’s DNA, ready to be transcribed
into new viruses, pretty sneaky, huh?
Well here’s the actual sneaky part—when the immune cells become activated, they start
transcribing and translating proteins needed for the immune response.
Ironically, this means that whenever the immune cell is exposed to something that causes it
to start up an immune response, like any infection, the immune cell ends up inadvertently transcribing
and translating new HIV viruses, which bud off from the cell membrane to infect more
cells.
Very sneaky indeed!
One thing to know is that HIV is notorious for making errors when it replicates and that
during an infection it can mutate to create slightly different strains of viruses.
These viruses are all still considered “HIV” but behave slightly differently from each
other and target different cells in the host, in fact that host cell preference is called
viral tropism.
So let’s start with HIV entering the body through sexual intercourse which is how it
typically spreads from person to person.
At this early point, during what we call acute infection, the R5 strain of HIV, which bind
to the CCR5 coreceptor will get into macrophages, dendritic cells, and T cells.
Usually dendritic cells hanging out in the epithelial or mucosal tissue where the virus
entered the body, capture the virus and migrate to the lymph nodes, where a lot of immune
cells live, and the R5 strain of HIV essentially has a field day, infecting T-helper cells,
macrophages, and more dendritic cells, which leads to a big spike in HIV replication and
the amount of virus found in the patient’s blood.
Patients typically experience flu-like or mononucleosis-like symptoms during the acute
infection.
In response, the immune system mounts a counterattack, and starts to control the amount of viral
replication, and the amount of virus in the blood declines to lower but still detectable
levels by 12 weeks—at which point the patient enters the chronic or clinically-latent phase,
which can last between 2 and 10 years.
If we also plot the amount of T cells alongside the amount of virus, we’ll see that they
loosely mirror each other, which makes total sense, right?
Initially you have a considerable decline in the acute phase until the immune system
mounts its counterattack.
After this point, even though there may not be any clinical signs or symptoms of the virus,
the virus is steadily chipping away at the immune system, and the number of viruses in
the blood slowly increases, while at the same time T cells slowly decrease, losing about
1-2 billion T cells every day.
During this chronic phase, T cell counts usually remain above 500 cells / mm3, about the size
of the head of a pin, and patients can still fight off other infections fairly well, although
some infections like tuberculosis become more common and severe.
Remember how HIV replication can create mutations?
Well during the chronic phase of HIV infection, it’s worth pointing out that some patients
develop an X4 strain of HIV which targets the CXCR4 coreceptor, which is essentially
only T-cells.
These X4 strains kind of lay low in the lymphoid tissues, and steadily destroy of CD4 T cells,
since about 90% of T cells are found in lymphoid tissue.
Not all patients develop the X4 strain, though, so it’s not completely clear what the presence
of this strain implies about the disease course.
When the body’s T cells drop low enough, between about 200 and 500 cells / mm3, patients
start experiencing symptoms like swollen lymph nodes, or lymphadenopathy, as well as relatively
minor infections like oral hairy leukoplakia, a hairy-looking white patch on the side of
the tongue caused by the same Epstein-Barr virus that causes mononucleosis, as well as
oral candidiasis, a yeast infection in the mouth.
As more T cells are lost, and the level falls below 200 cells / mm3, the immune system becomes
severely compromised and at this stage the condition has progressed from HIV disease
to AIDS.
At this point people experience things like persistent fever, fatigue, weight loss, and
diarrhea.
And the HIV count in the blood might increase significantly.
At this point, certain conditions start to develop that are said to be “AIDS-defining”,
such as recurrent bacterial pneumonia, pneumocystis pneumonia, and fungal infections like candidiasis
of the esophagus.
Other conditions include certain tumors and malignancies like Kaposi sarcoma which causes
lesions on the skin and other soft tissues, and primary lymphoma of the brain.
Many people with AIDS die from infections that a healthy immune system would typically
be able to fend off, like pneumocystis, cytomegalovirus, or mycobacterium avium complex.
Male-to-male transmission is the most common mode of transmission in the US, and male-to-female
is the most common mode in resource-limited settings.
Although less common, female-to-male transmissions occur as well since HIV is present in the
vaginal and cervical fluids of infected women.
In fact, over 75% of all cases of HIV are contracted from sexual intercourse.
The next most common means of transmission include things like intravenous drug abuse
and mother-to-child transmission, which can be via the placenta during delivery, or via
breast milk.
Other, much less common modes of transmission include accidental needlesticks, and use of
blood products like blood transfusions.
As far diagnosis goes, there are a few types of HIV tests that can be done—antibody tests,
antibody/antigen tests, and RNA/DNA tests.
Antibody tests look for antibodies that the body’s made against HIV.
Antigen tests look for the virus directly, so antibody/antigen tests detect both antibodies
to the virus as well as the virus itself.
RNA tests screen for viral RNA, so they also detect the virus directly, and DNA tests look
for copies of the viral RNA (since remember it’s a retrovirus so it copies its genetic
material into DNA).
For screening purposes, the recommended test is the antibody/antigen test, which is better
at identifying early infection.
It’s also recommended, if the first test is positive, to follow it with a confirmatory
test that looks for antibody or nucleic acids.
There’s currently no cure for AIDS; treatment however, can help somebody with AIDS live
longer, healthier lives and help reduce the risk of transmission.
The primary method is to use antiretroviral therapy, or ART.
ART isn’t a single medicine, but a combination of medicines that’s known as an HIV regimen.
These help slow down HIV replication, which gives the immune system a chance to recover
and help fight off other infections more effectively.